European Review for Medical and Pharmacological Sciences 2019; 23: 764-770

Acute HEV hepatitis:

clinical and laboratory diagnosis
G. MARRONE1, M. BIOLATO1, G. MERCURIO1, M.R. CAPOBIANCHI1,
A.R. GARBUGLIA2, A. LIGUORI1, G. VASSALLO1, A. GASBARRINI1,3,
L. MIELE1,3, A. GRIECO1,3
1
Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy
2
“Lazzaro Spallanzani” National Institute for Infectious Diseases, IRCCS, Rome, Italy
3
Università Cattolica del Sacro Cuore, Rome, Italy

Abstract. – OBJECTIVE: Hepatitis E Virus
(HEV) is probably the most common cause of
acute hepatitis worldwide. It has been regarded
for a long time as a disease limited to developing
countries. Recently, the refinement of diagnostic
techniques, on the one hand, and migratory flows,
on the other hand, have also led to the identifi-
cation of an increased number of HEV infections
in industrialized countries. Four HEV genotypes
have been identified across the world, with dif-
ferent epidemiological burdens and a wide range
of clinical presentations. Here, we report a case
series of acute HEV hepatitis observed in the last
three years in our hospital.
PATIENTS AND METHODS: We performed a
search for HEV IgM and IgG in all subjects admit-
ted for acute hepatitis without evidence of other
possible infectious, toxic or metabolic causes of
liver damage. In subjects with HEV IgM positivity,
the search for HEV-RNA was performed.
RESULTS: We diagnosed eight acute HEV
infections: 2 epidemic and 6 sporadic forms.
HEV-RNA was detected in serum in 2 cases.
CONCLUSIONS: HEV infection appears to be
a cause of acute hepatitis that we must keep in
mind even in developed countries.
Key Words
Hepatitis E virus, Jaundice, Viral hepatitis.
Introduction
For a long time, HEV hepatitis has been consid-
ered a peculiar viral infection typical of developing
countries, which is transmitted by the oro-faecal
route, mainly linked to poor sanitary conditions
and similar to HAV infection1-3. In developing
countries, such as India, Africa and Eastern coun-
tries, this infection is endemic, and it is estimated
to be responsible for 20-50% of cases of acute
hepatitis2. Since the 90s, with the sequencing of
the HEV genome and the development of serologic
diagnostic assays, it has been gradually recognized
that such infection is also present in industrialized
countries with prevalence rates reaching 21% in
the US4 and with a wider range in Europe (1.3%
of blood donors in Italy5, 52% in France2, 6.1% in
Scotland6, and 60.9% in Poland7). Recently, a Ger-
man study8 reported a prevalence of 0.12% HEV
RNA positive subjects among a cohort of blood
asymptomatic donors; thus, HEV hepatitis is cur-
rently considered the most common cause of acute
hepatitis in the world3,9. It is estimated that HEV
causes 20 million new infections per year and
70,000 deaths worldwide10,11. In Europe, the real
incidence of HEV infection is not fully elucidated,
but available data suggest regional differences and
a change in the epidemiology of the disease over
the time12. In general, the incidence of infection
seems to have increased in recent years, but this
phenomenon can be partly explained with a great-
er awareness in clinicians of HEV virus circulation
and with the improvement and greater availability
of diagnostic techniques13. Some regional hot-spots
have been identified across Europe; in Southwest
France, the Netherlands, Scotland, Western Ger-
many, the Czech Republic, Abruzzo in central
Italy, and Western/central Poland9. The reasons for
this epidemiological concentration of HEV cases
are not fully elucidated to date.
The epidemiological pattern of HEV infection
is divided into four zones: hyper-endemic and en-
demic zones with a prevalence of genotypes 1 and
2; a distinctive pattern zone, namely, Egypt, where
the genotype involved bears a peculiar subtype
(subtype 1) and the prevalence is higher among
young patients14; and the sporadic zone, involving
developed countries, where the prevalent genotypes
are 3 and 4. Epidemic forms are primarily human

764 Corresponding Author: Antonio Grieco, MD; e-mail: antonio.grieco@unicatt.it

 HEV case series
infections, while genotypes 3 and 4 are more likely
zoonotic, in which humans are accidental hosts15,16.
In developed countries, a well-documented source
of infection is the consumption of undercooked
infected pig meat, but infected pigs can also be a
possible source of environmental contamination
for lakes and rivers resulting in contamination of
seafood products and vegetables irrigated with
infected water17-19. The HEV epidemic form is
generally a severe disease3,20-24. In Europe, where
the most frequent agent is genotype 3, the infection
is usually clinically unapparent with signs and
symptoms of acute infections in less than 5% of
cases13. Genotype 3-related acute liver failure is
rare, although some cases have been reported in
Europe, mainly in Germany and France. HEV has
also been addressed as a possible cause of acute on
chronic liver failure25,26.
After acute infection, immunocompetent sub-
jects can clear the virus by developing non-steri-
lizing antibodies, so re-infection can occur even
if it is less probable than in non-immune subjects.
In immunocompromised subjects, chronicity has
been described with potential rapid fibrosis devel-
opment, leading to cirrhosis27,28.
In Italy, in real clinical practice, the ap-
pearance of acute hepatitis is rarely attributed
to HEV infection. Here, we report a series of
HEV-induced acute hepatitis cases observed in
our hospital.
Patients and Methods
From April 2015 until September 2017 in the
Gastroenterology Department of Policlinico Ge-
melli, Catholic University in Rome (Rome, Italy),
all subjects admitted for acute hepatitis were tested
for possible cause of infectious hepatitis, includ-
ing a work-up for HBV, HCV, HAV, EBV, CMV,
Herpes, leptospira, and salmonella. Non-infectious
causes of acute hepatitis were also investigated
including alcoholic, metabolic and toxic ones.
In subjects without the identification of a
clear cause of acute hepatitis, the search for
HEV antibodies was performed. The diagnos-
tic work-up for HEV infection was performed
in collaboration with Spallanzani Hospital in
Rome, (Rome, Italy). Anti-HEV IgM and an-
ti-HEV IgG were detected in sera using com-
mercial enzyme-linked immunosorbent assay
(ELISA) kits (DIA.PRO, diagnostic bioprobes,
Milan, Italy). HEV-RNA test and molecular
analysis were performed according to Garbu-
glia et al29. RNA was extracted from 400 µl
of plasma, using Qiasynphony (Qiagen, Hilden
GmbH, Germany). For HEV detection and gen-
otyping, RNA was subjected to RT-PCR, using
primers located in open reading frame 1 (ORF1)
of HEV. The sample with nested PCR products
was sequenced using 1981 and 1982 primers29.
A phylogenetic tree was produced based on the
best-fit model of nucleotide substitution provid-
ed by MEGA6 software30. The diagnosis of HEV
acute infection was formulated in the presence
of HEV IgM positivity. In all subjects with pos-
itive IgM, blood and stool samples were tested
for HEV-RNA.
Results
We diagnosed eight acute HEV infections: all
patients were admitted because of a clinical and
laboratory diagnosis of acute hepatitis. In Table
I, demographic, clinical patterns of presentation,
ethnicity, potential risk factors and outcomes
were reported. The pattern of liver damage at
presentation was cholestatic in 3 cases and hepa-
tocellular in 5 cases. Clinical presentation was
jaundice in 4 cases, flu-like symptoms in 1 case
and abdominal symptoms in 3 cases. In 2 cases,
the clinical course was complicated by acute
renal failure requiring haemodialysis. An under-
lying chronic liver disease was present in 3 cases
including two cases of alcoholic liver cirrhosis
(Case 3 and 5) and an autoimmune chronic hep-
atitis (Case 6). A percutaneous liver biopsy was
performed in case 3 and case 6 and revealed acute
cholestatic hepatitis. The search for other possible
causes of acute liver disease, including infectious,
toxic and metabolic causes was negative in all
subjects. The search for cryoglobulins was nega-
tive in all cases. Table II reports the liver function
tests performed during hospitalization.
All the subjects presented a positive HEV
IgM and IgG while HEV-RNA was detected
in serum in 2 subjects, revealing genotype 1 in
the first case (epidemic form) and genotype 3 in
the second case (sporadic form). HEV-RNA in
stools was absent in all cases. Seven patients had
complete clinical and laboratory recovery from
the infection with no evidence of chronicity. One
subject with a sporadic form of acute HEV died
because of sepsis following acute on chronic liver
failure and acute renal failure. The median hospi-
tal stay was 23.6 days (range 9-47). Interestingly,
in four cases, drug-induced liver injury (DILI)
765
 A. Liguori, G. Vassallo, A. Gasbarrini, L. Miele, A. Grieco, et al

Table I. Demographic of study population.

Age Sex Etnicity Pattern Epi- Hospital ICU Risk HEV HEV-RNA Out-
demic/ stay stay factors geno- serum come
Sporadic (days) (days) type detection

Case 1 72 M C. Chol. Spor. 10 0 absent n.a. no resolved

Case 2 61 M C. Hep Spor. 17 0 present 3 yes resolved
Case 3 64 M C. Chol. Spor. 47 0 present n.a. no deceased
Case 4 69 F C. Chol. Spor. 13 0 absent n.a. no resolved
Case 5 76 M C. Hep Spor. 45 0 absent n.a. no resolved
Case 6 29 M C. Hep Spor. 9 0 present n.a. no resolved
Case 7 29 M A. Hep Epid. 12 0 absent n.a. no resolved
Case 8 29 M A. Hep Epid. 36 6 present 1 yes resolved

Legend. ALT: Alanine aminotransferase; INR: International Normalized Ratio; ICU: Intensive Care Unit, C: Caucasian; A:
Asiatic; Spor: Sporadic; Epid: Epidemic; Chol: Cholestatic; Hep: Hepatocellular; N.A.: Not Available.

was suspected. At discharge, all patients un-
derwent a follow-up in the outpatient clinic that
demonstrated complete resolution of laboratory
abnormalities within three months. No patient
showed signs of chronic disease.
Discussion
The acute course of HEV is characterized by
a wide range of manifestations, ranging from
asymptomatic and self-limiting forms to severe
forms with possible fatal outcomes3,31. Recently,
de novo autoimmune hepatitis secondary to HEV
acute infection has been reported32. Acute HEV
infection is characterized by fleeting HEV-RNA
positivity in stool and serum, with longer IgM
serum detection, often for some months after
infection33, while serum IgG may last for years.
Particularly severe forms of acute HEV infec-
tions have been described in pregnant women,
in the elderly, in subjects with pre-existing liver
disease and in immunocompromised subjects34-37.
In immunocompromised patients, there was also
an increased tendency to chronicity and a higher
prevalence of HEV genotype 3 infection. Chronic
HEV hepatitis, although rare, is characterized by
a persistent elevation of serum aminotransferases,
with persistent HEV-RNA detection in the serum27.
In this paper, we report eight cases of severe
acute hepatitis secondary to HEV infection, as
confirmed by HEV IgM detection in all cases.
The only patient who died had pre-existing liver
disease. All patients presented with a picture of
acute icteric hepatitis requiring hospitalization.
HEV-RNA serum positivity was observed only in
two cases, an epidemic and a sporadic form, re-
vealing genotypes 1 and 3, respectively. There was
no identification of HEV-RNA in stool samples38.
Two of the observed cases were considered ep-
idemic forms because of recent travel in endemic
areas (Pakistan and Bangladesh). In one of these

Table II. Laboratory parameters during the hospitalization.

ALT (UI/L) Bilirubin INR at Creatinine ALT (UI/L) Bilirubin INR at Creatinine
at (mg/dl) at admission (mg/dl) at at (mg/dl) at discharge (mg/dl) at
admission admission admission discharge discharge discharge

Case 1 4335 15.5 2.1 1 14 1.1 1.1 0.77

Case 2 2391 6.9 1.2 0.9 92 7.4 1.12 0.91
Case 3 936 17.6 1 1 22 32 1.79 4.94
Case 4 1047 5.6 1 1 141 1.9 1.03 0.8
Case 5 2215 12.5 1.4 0.9 99 19.8 1.25 0.79
Case 6 1437 17.3 0.9 0.5 850 7.5 1.3 0.81
Case 7 4884 4.8 0.8 0.4 547 4 1.12 0.72
Case 8 1951 2.8 1.8 0.9 249 4.3 1 2.67

Legend. ALT: Alanine aminotransferase; INR: international normalized ratio.

766
 HEV case series
cases, the risk factor for infection was also iden-
tified (consumption of undercooked local poultry
meat) and HEV genotype 1 was identified. The
remaining six cases were considered autochtho-
nous forms with risk factors for HEV infection in 3
cases. HEV genotype 3 was identified in one case.
An explanation for the negative serum HEV-RNA
in most of the observed subjects probably could be
due to the delayed time of search for HEV infec-
tion. In fact, in the presence of evident risk factors
for HEV infection, such as recent travel to a high-
risk country or the consumption of unsafe foods,
serological and molecular HEV testing was part
of the initial laboratory work-up. In the remaining
cases, possible HEV infection was considered only
in a subsequent phase of the diagnostic process.
It is well known that the HEV-RNA is detect-
able in the blood and stool in the early stages of
infection, but it is difficult to detect after diagnostic
delay due to a lack of clinical suspicion, especially
in industrialized countries14. Davern et al39, analys-
ing a cohort of suspected drug-induced liver injury,
reported that 5/9 HEV-IgM positive subjects were
HEV-RNA negative, estimating that the positivity
of HEV-RNA was detectable, on average, in 60% of
cases, even if performed at the onset of symptoms.
All patients showed a clinical picture of severe
acute icteric hepatitis at admission. In developed
countries, the picture of an acute icteric hepatitis in
patients lacking evidence of common viral infec-
tion, (HAV, HBV, HCV) or metabolic and genetic
liver disease, commonly orients the search for xe-
nobiotics or drug-induced liver injury (DILI), while
the presence of acute HEV infection is rarely taken
into account40-42. In our series, a DILI was first
considered in 50% of cases. This result is not sur-
prising considering that the presence of prodromal
symptoms of acute viral infections, such as flu-like
symptoms or abdominal symptoms, can lead to the
assumption of antipyretics or antibiotics, which are
the most implied class of drugs in DILI43-45, thus
leading to misinterpretation of the clinical picture.
Davern et al39, on behalf of DILIN, reported
that of 50 out of 318 subjects (16%) enrolled for
suspected drug-induced liver injury (DILI) were
positive for HEV IgG while 9 out of 318 (3%)
were also IgM positive. In a retrospective Euro-
pean study, HEV-RNA was identified in 3 out
of 157 (2%) cases. Acute HEV hepatitis may be
particularly severe and sometimes fatal in im-
munocompromised and elderly subjects. The hy-
per-acute form has been described in individuals
with pre-existing liver disease, even if asympto-
matic3,35,46. In our series, a subject with pre-ex-
isting, undiagnosed liver cirrhosis died because
of sepsis following acute-on-chronic-liver failure.
This patient also presented acute renal failure with
the need for renal replacement therapy. Another
subject in our series presented acute renal failure
during the course of acute HEV with the need for
haemodialysis and complete normalization of renal
function two months later. This subject presented
an epidemic form, and genotype 1 was identified.
It is well known that anti-HEV seroprevalence
is high in patients undergoing substitutive dialyt-
ic treatment47 with a percentage of 40% HEV-se-
ropositive among kidney transplant candidates in
a French cohort48. The cause of this association is
not fully understood to date. The development of
glomerular diseases in a subject with acute HEV
infection has been described in the literature in
patients infected by GT349-51. The role of HEV
infection in the genesis of renal damage is still
unclear, although it is possible to hypothesize a
direct cytopathic effect by virus replication in
the kidney, as suggested by some experimental
experiences52,53, or an immune-mediated mecha-
nism similar to HCV-associated kidney diseases.
Two patients in our series experienced acute
kidney injury: in one case bilirubin levels reached
dramatically high values (70 mg/dl). Although it
is well known that HEV infection may cause glo-
merulonephritis with or without cryoglobuline-
mia50,54, we believe that our patients experienced
bilirubin-related kidney damage, rather than a
direct virus-related effect because no cryoglob-
ulinemia was found and renal failure recovered
with no specific therapy.
The pathogenesis of renal damage in patients
with severe hyperbilirubinemia is still not fully
elucidated but is probably multifactorial. Romano
et al55 have identified three possible pathogenetic
factors for renal damage in the course of prolonged
hyperbilirubinemia: haemodynamic changes, ob-
struction by bile salts, and inflammation.
Despite the severity of clinical onset, we did
not observe any significant extrahepatic manifes-
tations, in contrast to reports in the literature, such
as aplastic anemia, arthritis or pancreatitis56,57.
Conclusions
HEV is also a widespread infection in devel-
oped countries, such Italy. All patients presenting
with a clinical and laboratory picture of acute
hepatitis with no evidence of a clear cause of liver
damage must be tested for HEV.
767
 A. Liguori, G. Vassallo, A. Gasbarrini, L. Miele, A. Grieco, et al
 
Acknowledgements
This work was partially supported by the European Union
Seventh Framework Programme (FP7/2007-2013) under
Grant Agreement No. 278433-PREDEMICS and Ricerca
Corrente Fund.
 
Conflict of Interests
 
The authors certify that they have NO affiliations with or
involvement in any organization or entity with any financial
interest or non-financial interest in the subject matter or
materials discussed in this manuscript.
 
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